The objective of the present investigation was to prepare colon targeted piroxicam loaded Eudragit S 100 microspheres and evaluate its properties. The microspheres were prepared by using "O/O solvent evaporation" technique. The formulation was optimized by investigating the influence of various process variables like stirring speed, drug: polymer ratio and percentage of emulsifier on the fabrication and the prepared microspheres were evaluated for in vitro properties. Piroxicam loaded Eudragit S 100 microspheres were successfully prepared using "O/O solvent evaporation" method. Microspheres prepared using 1:5 drug: polymer ratio, with a stirring speed of 1000 rpm, and 1.0% w/v concentration of emulsifying agent was selected as an optimized formulation. In vitro drug release were performed in pH 1.2 (0.1N HCl) for 2h and in pH 6.8 phosphate buffer for next 2h followed by 7 pH phosphate buffer up to 24 h. The release pattern of drug was slow at low pH values and increased on rise in pH. The drug release followed Higuchi model.